Abstract Alcoholic (AH) is a leading cause of liver-related morbidity and mortality with a remarkable paucity of effective therapeutics. This application represents a coordinated submission of several NIAAA-funded consortia which have come together as the Alcoholic Hepatitis Network (AlcHepNet) to better understand AH and develop novel effective and safe therapy for severe AH. The overarching aims of this consortium are to: (1) perform studies to better understand the pathogenesis and main determinants of outcome, particularly in severe AH, (2) identify novel targets for therapy of AH, and (3) perform phase 2B studies of compounds that are already available and can be repurposed as safe and effective therapy for severe AH. Under the umbrella of these larger aims, the aims of this proposal are: 1. To conduct a prospective, multicenter, observational study of patients with AH and suitable controls that serves as the foundation for conducting novel mechanistic and therapeutic studies. We will consolidate and extend our longitudinal database of (1) clinical and laboratory information and (2) a bio-sample repository from subjects with AH of varying severity and matched-controls. This database will: (a) provide unique information on the outcomes and pathobiology of AH, (b) support translational research designed to identify novel targets for treatment, and (c) be used to generate systems biology based informatics-integrated databases that will serve as a resource for all researchers interested in AH. 2. To perform a multicenter prospective, randomized phase 2B clinical trial of G-CSF and Anakinra versus standard medical therapy with Prednisolone in patients with severe AH. This aim will test the hypothesis that both active treatment arms with G-CSF and the IL-1 receptor antagonist Anakinra are superior to the stardard of care (i.e. prednisolone) in patients with severe AH. The choice of these agents is based on: (1) literature demonstrating a role for inflammation and inflammasome activation in severe AH, (2) several pilot studies demonstrating therapeutic benefit with G-CSF, (3) interim analysis of an ongoing trial suggesting a mortality benefit with Anakinra in patients with AH. This phase 2B efficacy trial will be conducted across nine clinical centers and coordinated by a Data Coordinating Center (DCC). The primary endpoint will be mortality at day 90. The investigators and the AlcHepNet is uniquely positioned to perform the proposed study given substantial breadth and depth of expertise related to AH, clinical trial conduct, and therapeutic development. By testing promising therapies for AH and concurrently collecting well annotated patient samples and datasets, this proposal will have a strong and lasting impact on the field.